HLA-driven convergence of HIV-1 viral subtypes B and F toward the adaptation to immune responses in human populations.
BACKGROUND
Cytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1.


RESULTS
We undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naïve HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes.


CONCLUSIONS
Across HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate.
Dilernia
Dario Alberto
DA
Centro Nacional de Referencia para el SIDA, Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Capital Federal, Buenos Aires, Argentina.
Jones
Leandro
L
Rodriguez
Sabrina
S
Turk
Gabriela
G
Rubio
Andrea E
AE
Pampuro
Sandra
S
Gomez-Carrillo
Manuel
M
Bautista
Christian T
CT
Bautista
Christian
C
Deluchi
Gabriel
G
Benetucci
Jorge
J
Lasala
María Beatriz
MB
Lourtau
Leonardo
L
Losso
Marcelo Horacio
MH
Perez
Héctor
H
Cahn
Pedro
P
Salomón
Horacio
H
D000956:Antigens, Viral / Q000235:genetics; D005075:Biological Evolution; D000939:Epitopes / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D007109:Immunity; D015233:Models, Statistical; D009154:Mutation; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000956:Antigens, Viral; D000939:Epitopes; D015683:Gene Products, gag; D006680:HLA Antigens; D015235:HLA-B Antigens